In the mammalian brain, a number of genes essential for circuit development and synaptic plasticity are controlled by neuronal activity. However, the underlying molecular mechanisms are incompletely understood. HDAC4 is a member of the class IIa histone deacetylase family of nuclear repressors that shuttle between the nucleus and cytoplasm and interact with tissue-specific transcription factors (TFs) in a signal-regulated manner. Human genetic studies have shown that mutations in the HDAC4 locus cause mental retardation, but the consequences of HDAC4 deficiency on neural circuits remain elusive. Our recent exciting observations support the hypothesis that HDAC4 is a molecular substrate for NMDA receptor-dependent transcriptional control of synaptic strength. We found that, in cultured neurons, HDAC4 represses multiple synapse-related genes thereby affecting the structural organization of central synapses and their physiological properties. Furthermore, NMDA receptors prevent the binding of HDAC4 to neuronal chromatin and TFs, and mis- regulation of this transcriptional pathway in the mouse forebrain impairs neurotransmission and spatial memory. We have developed a comprehensive genetic toolbox and assembled a team of qualified investigators to rigorously investigate the outcomes of nuclear HDAC4 signaling in mouse models. In SA1, the interplay between synaptic inputs and HDAC4 repressor activity will be tested in mutant animals that are deficient for NMDA receptors, and in a new unique mouse strain that enables acute drug-inducible manipulation of synaptic neurotransmitter release from specific neuronal types in vivo. In SA2, we will use both genetic loss- and gain- of-function approaches to define the role of HDAC4 in regulating basal neurotransmission and experience- dependent forms of synaptic plasticity in the Dentate Gyrus (DG), a brain region that relays cortical information into the hippocampus and promotes several cognitive tasks. To this end, we will interrogate mice that either lack native HDAC4 due to conditional gene silencing, or express a constitutively nuclear repressor mutant in the wildtype background. Finally, imaging experiments directed towards SA3 will test how nuclear HDAC4 signaling impacts the connectivity between excitatory and inhibitory neurons in the DG, and the architectures of their functional synapses. These studies will gain significant new insights into the mechanisms of experience-dependent transcriptional silencing/de-repression in the brain, elucidate the role of HDAC4 in controlling synaptic function, and provide a molecular explanation for a rare human disease.